High-Flow Vascular Malformations in Children.

Children can have a variety of intracranial vascular anomalies ranging from small and incidental with no clinical consequences to complex lesions that can cause substantial neurologic deficits, heart failure, or profoundly affect development. In contrast to high-flow lesions with direct arterial-to-venous shunts, low-flow lesions such as cavernous malformations are associated with a lower likelihood of substantial hemorrhage, and a more benign course. Management of vascular anomalies in children has to incorporate an understanding of how treatment strategies may affect the normal development of the central nervous system. In this review, we discuss the etiologies, epidemiology, natural history, and genetic risk factors of three high-flow vascular malformations seen in children: brain arteriovenous malformations, intracranial dural arteriovenous fistulas, and vein of Galen malformations

Malaria Life Cycle Intensifies Both Natural Selection and Random Genetic Drift

Analysis of genome sequences of 159 isolates of Plasmodium falciparum from Senegal yields an extraordinarily high proportion (26.85%) of protein-coding genes with the ratio of nonsynonymous to synonymous polymorphism greater than one. This proportion is much greater than observed in other organisms. Also unusual is that the site-frequency spectra of synonymous and nonsynonymous polymorphisms are virtually indistinguishable. We hypothesized that the complicated life cycle of malaria parasites might lead to qualitatively different population genetics from that predicted from the classical Wright-Fisher (WF) model, which assumes a single random-mating population with a finite and constant population size in an organism with nonoverlapping generations. This paper summarizes simulation studies of random genetic drift and selection in malaria parasites that take into account their unusual life history. Our results show that random genetic drift in the malaria life cycle is more pronounced than under the WF model. Paradoxically, the efficiency of purifying selection in the malaria life cycle is also greater than under WF, and the relative efficiency of positive selection varies according to conditions. Additionally, the site-frequency spectrum under neutrality is also more skewed toward low-frequency alleles than expected with WF. These results highlight the importance of considering the malaria life cycle when applying existing population genetic tools based on the WF model. The same caveat applies to other species with similarly complex life cycles.Organismic and Evolutionary Biolog

Evaluation of time-resolved whole brain flat panel detector perfusion imaging using RAPID ANGIO in patients with acute stroke: comparison with CT perfusion imaging.

BACKGROUND In contrast to conventional CT perfusion (CTP) imaging, flat panel detector CT perfusion (FD-CTP) imaging can be acquired directly in the angiosuite. OBJECTIVE To evaluate time-resolved whole brain FD-CTP imaging and assess clinically important qualitative and quantitative perfusion parameters in correlation with previously acquired conventional CTP using the new RAPID for ANGIO software. METHODS We included patients with internal carotid artery occlusions and M1 or M2 occlusions from six centers. All patients underwent mechanical thrombectomy (MT) with preinterventional conventional CTP and FD-CTP imaging. Quantitative performance was determined by comparing volumes of infarct core, penumbral tissue, and mismatch. Eligibility for MT according to the perfusion imaging criteria of DEFUSE 3 was determined for each case from both conventional CTP and FD-CTP imaging. RESULTS A total of 20 patients were included in the final analysis. Conventional relative cerebral blood flow (rCBF) 6 s versus FD-CTP Tmax >6 s and CTP mismatch versus FD-CTP mismatch showed more variability (R2=0.57, and R2=0.33, respectively). Based on FD-CTP, 16/20 (80%) patients met the inclusion criteria for MT according to the DEFUSE 3 perfusion criteria, in contrast to 18/20 (90%) patients based on conventional CTP. The vessel occlusion could be correctly extrapolated from the hypoperfusion in 18/20 cases (90%). CONCLUSIONS In our multicenter study, time-resolved whole brain FD-CTP was technically feasible, and qualitative and quantitative perfusion results correlated with those obtained with conventional CTP

Radiological and clinical features of vein of Galen malformations.

BackgroundVein of Galen malformations (VOGMs) are rare and complex congenital arteriovenous fistulas. The clinical and radiological features of VOGMs and their relation to clinical outcomes are not fully characterized.ObjectiveTo examine the clinical and radiological features of VOGMs and the predictors of outcome in patients.MethodsWe retrospectively reviewed the available imaging and medical records of all patients with VOGMs treated at the University of California, San Francisco between 1986 and 2013. Radiological and clinical features were identified. We applied the modified Rankin Scale to determine functional outcome by chart review. Predictors of outcome were assessed by χ(2) analyses.ResultsForty-one cases were confirmed as VOGM. Most patients (78%) had been diagnosed with VOGM in the first year of life. Age at treatment was bimodally distributed, with predominantly urgent embolization at <10 days of age and elective embolization after 1 year of age. Patients commonly presented with hydrocephalus (65.9%) and congestive heart failure (61.0%). Mixed-type (31.7%) VOGM was more common in our cohort than purely mural (29.3%) or choroidal (26.8%) types. The most common feeding arteries were the choroidal and posterior cerebral arteries. Transarterial embolization with coils was the most common technique used to treat VOGMs at our institution. Functional outcome was normal or only mildly disabled in 50% of the cases at last follow-up (median=3 years, range=0-23 years). Younger age at first diagnosis, congestive heart failure, and seizures were predictive of adverse clinical outcome. The survival rate in our sample was 78.0% and complete thrombosis of the VOGM was achieved in 62.5% of patients.ConclusionsVOGMs continue to be challenging to treat and manage. Nonetheless, endovascular approaches to treatment are continuing to be refined and improved, with increasing success. The neurodevelopmental outcomes of affected children whose VOGMs are treated may be good in many cases

Pediatric intracranial dural arteriovenous fistulas: age-related differences in clinical features, angioarchitecture, and treatment outcomes.

OBJECTIVE Intracranial dural arteriovenous fistulas (DAVFs) are rare in children. This study sought to better characterize DAVF presentation, angioarchitecture, and treatment outcomes. METHODS Children with intracranial DAVFs between 1986 and 2013 were retrospectively identified from the neurointerventional database at the authors' institution. Demographics, clinical presentation, lesion angioarchitecture, treatment approaches, angiographic outcomes, and clinical outcomes were assessed. RESULTS DAVFs constituted 5.7% (22/423) of pediatric intracranial arteriovenous shunting lesions. Twelve boys and 10 girls presented between 1 day and 18 years of age; boys presented at a median of 1.3 years and girls presented at a median of 4.9 years. Four of 8 patients ≤ 1 year of age presented with congestive heart failure compared with 0/14 patients > 1 year of age (p = 0.01). Five of 8 patients ≤ 1 year old presented with respiratory distress compared with 0/14 patients > 1 year old (p = 0.0021). Ten of 14 patients > 1 year old presented with focal neurological deficits compared with 0/8 patients ≤ 1 year old (p = 0.0017). At initial angiography, 16 patients harbored a single intracranial DAVF and 6 patients had 2-6 DAVFs. Eight patients (38%) experienced DAVF obliteration by the end of treatment. Good clinical outcome (modified Rankin Scale score 0-2) was documented in 77% of patients > 1 year old at presentation compared with 57% of patients ≤ 1 year old at presentation. Six patients (27%) died. CONCLUSIONS Young children with DAVFs presented predominantly with cardiopulmonary symptoms, while older children presented with focal neurological deficits. Compared with other pediatric vascular shunts, DAVFs had lower rates of angiographic obliteration and poorer clinical outcomes

Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report.

Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of ∼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.Bloodwise (grant number 15037) funded the majority of this study. Genetic sequencing was funded by 14M Genomics, a start-up company that ceased trading February 2016. DJH was funded by a clinician scientist fellowship from the MRC and receives core funding from Wellcome and MRC to the Wellcome-MRC Cambridge Stem Cell Institute. Some of the analysis in this study was performed on the “Viking” high performance computing cluster at the University of York.1